Uncoupling of muscarinic cholinergic phosphoinositide signals in senescent cerebral cortical and hippocampal membranes.
Muscarinic-cholinergic signals in brain are mediated in part through the hydrolysis of phosphoinositides (PtdIns) by phospholipase C (PLC). To test the hypothesis that muscarinic PtdIns signals change during aging, membranes were prepared from the cerebral cortex and hippocampus of young (4-6 months old), middle aged (8-10 months old) and senescent (24-26 months old) Fisher 344 rats. Carbachol dose-dependently increased [3H]-PtdIns hydrolysis in both brain regions in all three age groups, however, in senescent rats the maximal response was decreased to 69.26 +/- 4.33% (p < 0.01) in cortex and to 48.29 +/- 2.55% (p < 0.01) in hippocampus of young rat values. In contrast to the decrease in carbachol-stimulated phosphoinositide hydrolysis, calcium-stimulated phosphoinositide hydrolysis was not altered. GTP gamma S also dose-dependently increased [3H]-PtdIns hydrolysis in membranes from all three age groups through G-protein-PLC activation. Similar to carbachol, GTP gamma S-activated [3H]-PtdIns hydrolysis was reduced approximately 40% in senescent rats membranes. Muscarinic receptor (mAChR) density, as determined by [3H]-QNB binding decreased slightly in cortical membranes, but not in hippocampal membranes. These data suggest that muscarinic stimulated [3H]-PtdIns responses are decreased in senescent brain primarily due to an uncoupling of the receptor-G-protein and/or G-protein-PLC link, although decreases in receptor density may also contribute to reduced muscarinic [3H]-PtdIns signaling.
Ayyagari
P V
PV
Center for Alcohol Studies, University of North Carolina-Chapel Hill School of Medicine 27599-7178, USA.
Gerber
M
M
Joseph
J A
JA
Crews
F T
FT
D000375:Aging; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism*; D006868:Hydrolysis; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D011976:Receptors, Muscarinic / Q000502:physiology*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism
D018721:Muscarinic Agonists; D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002217:Carbachol; D010738:Type C Phospholipases; D002118:Calcium